Bipolar disorder is a major psychiatric disorder affecting approximately 1-2% of the population. Numerous family studies and twin studies support a substantial genetic component. We have conducted a genome scan that indicated the presence of a susceptibility locus on 22q with a maximum tod score of 3.8 at the marker D22S278. The evidence for linkage on the chromosome extended over nearly 15 Mb and suggested a possible second peak 10 Mb telomeric at the gene for G protein receptor kinase 3 (GRK3). Both of these two regions on 22q have also been reported to be linked or associated to both bipolar disorder and schizophrenia. This suggests that one or more genes may exist on this chromosome that predisposes to both disorders. Our results are consistent with recent meta-analyses of genome scans of bipolar disorder which found 22q to be one of the most robust linkage findings in the genome. Though the strongest Iod score results in our study initially were to the D22S278 locus, another linkage study in a second sample, as well as, animal microarray studies have supported the role of the GRK3 locus. We have also identified several possible functional SNPs in the promoter of this gene and shown them to be associated to bipolar disorder in two independent samples. It is our hypothesis, that there are two distinct loci for bipolar disorder on this chromosome. We propose to 1) confirm the role of GRK3 as a susceptibility gene by additional association studies and functional studies of gene expression; and 2) identify the susceptibility locus near D22S278. 250 kb surrounding the GRK3 gene will be sequenced in bipolar subjects from families linked to the GRK3 locus. 200 SNPs will be genotyped across a 1 Mb interval including the GRK3 locus in a sample of 800 Caucasian bipolars and 800 Caucasian controls. We hypothesize a defect in transcriptional regulation of the GRK3 gene that results in a failure of receptor desensitization. The regulation of gene expression of GRK3 will be tested in lymphoblastoid cell lines from bipolar patients and in a transfection reporter promoter assay in a neuroblastoma cell line. In order to identify candidate genes near D22S278, 500 SNPs will be genotyped at a 10 kb density across 5 Mb in this region. Positional candidate genes will then be sequenced and genotyped at higher density in order to identify those associated with illness.